This Article Abstract Full Text (PDF) All Versions of this Article: theoncologist.2008-0049v1 13/7/807    most recent eLetters: Submit a response to this article Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Ko, E. Articles by Goodman, A. Search for Related Content PubMed PubMed Citation Articles by Ko, E. Articles by Goodman, A.

Gynecologic Oncology

Gemcitabine Pulmonary Toxicity in Ovarian Cancer

Massachusetts General Hospital, Department of Gynecologic-Oncology, Boston, Massachusetts, USA

Key Words. Gemcitabine • Ovarian cancer • Chemotherapy • Pulmonary toxicity • ARDS

Correspondence: Annekathryn Goodman, M.D., Massachusetts General Hospital, Gillette Center for Women's Cancer, Yawkey 9E-9050, 32 Fruit Street, Boston, Massachusetts 02114-2617, USA. Telephone: 617-724-5242; Fax: 617-726-1949; e-mail:Agoodman{at}partners.org

Received February 26, 2008; accepted for publication June 2, 2008; first published online in THE ONCOLOGIST Express on July 9, 2008.

Disclosure: The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors, planners, independent peer reviewers, or staff managers.

	LEARNING OBJECTIVES

Top Learning Objectives Abstract Introduction Case Report Discussion Author Contributions References

 
After completing this course, the reader should be able to:

1. Describe the role of gemcitabine in the management of recurrent ovarian cancer.
   
2. Evaluate the signs and symptoms of gemcitabine pulmonary toxicity.
   
3. Engage in the diagnosis, differential diagnosis, and intervention of gemcitabine pulmonary toxicity.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction Case Report Discussion Author Contributions References

 
Background. A case of gemcitabine-induced lung toxicity is reported in a woman with stage IIIc ovarian papillary serous carcinoma.

Case. An 83-year-old woman with stage IIIc ovarian serous papillary carcinoma diagnosed in 2001 underwent suboptimal cytoreductive surgery followed by carboplatin–paclitaxel chemotherapy. Initially in remission following chemotherapy, the disease subsequently progressed over the next 5 years. The patient received gemcitabine palliative chemotherapy. She developed significant pulmonary toxicity consistent with drug-induced interstitial pneumonitis, which improved with steroid therapy.

Conclusion. Gemcitabine, a second-line chemotherapy agent for the treatment of ovarian cancer, may rarely cause a serious or even fatal condition of pulmonary lung toxicity.

	INTRODUCTION

Top Learning Objectives Abstract Introduction Case Report Discussion Author Contributions References

 
Gemcitabine (2',2'-difluoro-s'-deoxycytidine; Gemzar; Eli Lilly, Indianapolis, IN), a pyrimidine nucleoside analogue similar to cytarabine, is increasingly used as a second-line agent for ovarian cancer. Gemcitabine inhibits DNA synthesis both by halting DNA replication through the incorporation of its active form into DNA and also by inhibiting ribonucleotide reductase and deoxycytidine monophosphate deaminase [1, 2]. It is administered as a prodrug that becomes phosphorylated by deoxycytidine kinase to the active diphosphate and triphosphate forms [3]. Gemcitabine has been used to treat cancers including non-small cell lung, pancreatic, urothelial, breast, and ovarian cancer [1, 3]. Common side effects include nausea and vomiting, rash, fever, reversible elevation of liver transaminases, flu-like symptoms, and peripheral edema [3, 4]. Myelosuppression is the most common dose-limiting toxicity [3].

Overall, gemcitabine is relatively well tolerated. However, a few reports have described gemcitabine-induced lung toxicity [1–7]. Recently, this toxicity was reported in patients with ovarian cancer [2, 8, 9]. Although up to 23% of patients treated with gemcitabine may develop dyspnea, a small fraction of patients may develop severe dyspnea, diffuse alveolar damage, acute respiratory distress syndrome, interstitial pneumonitis, or noncardiogenic pulmonary edema requiring steroid therapy [2, 4, 5, 8–10]. The incidence of grade 4 lung toxicity, called "Gemzar lung," lies between 0.06%, reported by an industry study based on commercial exposure worldwide, and 8%, reported in several case study reviews. The outcome of Gemzar lung varies from recovery to death [2–5, 9]. In one review, the mortality rate was 20% [8]. The age profile of gemcitabine pulmonary toxicity, described in adults 31–85 years old with the majority of patients aged 50–60 years, may reflect the predominance of cancer diagnoses during these decades. The slight preponderance for males over females may also parallel the prevalence of cancer in these populations (primarily lung cancer groups) [2, 3, 7].

Presently, severe gemcitabine lung toxicity, Gemzar lung, is a rare but serious condition that is a diagnosis of exclusion. We describe the case of a woman treated for ovarian cancer with gemcitabine lung toxicity.

	CASE REPORT

Top Learning Objectives Abstract Introduction Case Report Discussion Author Contributions References

 
An 83-year-old woman with stage IIIc ovarian serous papillary carcinoma was admitted to the hospital with shortness of breath. She had hypertension and emphysema, but no significant cardiac history and had quit smoking >15 years ago. She formerly smoked four packs a day. At her initial cancer diagnosis in March of 2001, she underwent an exploratory laparotomy, modified radical hysterectomy, bilateral salpingoophorectomy, pelvic side wall dissection, rectosigmoid resection, and sigmoid to low rectal end to end reanastomosis. Intraoperative findings included a large pelvic mass densely adhered to the uterus and right pelvic side wall, cecum, and rectum with positive pelvic and periaortic lymph nodes.

A complete clinical remission was achieved with six cycles of carboplatin and paclitaxel. Her cancer recurred, and she underwent additional therapy over the next 4 years, including pegylated liposomal doxorubicin, tamoxifen, anastrozole, pegylated liposomal doxorubicin again, and carboplatin, for which she required interval desensitization of platinum.

Because of progressive disease and an excellent performance status, she chose palliative gemcitabine chemotherapy. She received gemcitabine with a dosing regimen of 800 mg/m² on days 1, 14, and 28, every 4 weeks for a completion of 1.5 cycles.

Her treatment course was complicated by the development of bilateral pulmonary emboli in November of 2005, for which she was treated with dalteparin therapy with a bridge to warfarin, as well as a Greenfield inferior vena cava filter. A pulmonary embolus (PE) protocol computed tomography (CT) performed thereafter revealed a decreased PE burden and emboli that had peripheralized.

Eight weeks after the initiation of gemcitabine, the patient was admitted for shortness of breath, particularly with exertion, in the absence of chest pain. Her review of systems was otherwise negative. On exam, she was afebrile, with a pulse of 71 and blood pressure of 112/59 mmHg. She was breathing with a respiratory rate of 18 and maintaining an oxygen saturation level of 97% on room air. She had diffusely decreased breath sounds, but no crackles, wheezes, or rhonchi. Her cardiac exam was normal. Laboratory studies were significant for a blood urea nitrogen of 30 mg/dl and creatinine of 1.2 mg/dl (her baseline), normal liver enzymes (aspartate aminotransferase, 58 u/l; alanine aminotransferase, 27 u/l), and CBC (WBC, 11.1 x 10³/µl, hematocrit, 34.5%). Her cancer antigen 125 was 3,675 u/ml. She was subtherapeutic on warfarin. She restarted dalteparin and transitioned to daily injections of fondaparinox for ease of administration. The admission chest x-ray (CXR) (Fig. 1A) showed hyperinflated clear lungs consistent with the patient's known emphysema. A concurrent chest CT demonstrated known pulmonary emboli that had decreased in burden compared with prior studies (Fig. 1B) and clear lungs (Fig. 1C). Given a fever of 101.3°F on hospital day 2, an abdominal CT scan was performed, which showed increased liver metastasis. Other etiologies for infection were ruled out and she was presumed to have tumor fever. By hospital day 4, the patient's dyspnea had subjectively improved and she was discharged home.

View larger version (58K): [in this window] [in a new window]   Figure 1. Imaging at presentation. Posterior–anterior chest radiograph (A) shows clear lungs with elevated volume consistent with the patient's known emphysema. Soft tissue window image from a contrast-enhanced chest computed tomography (B) demonstrates partially obstructive thrombi in the subsegmental pulmonary arteries. Lung window image from the same study (C) demonstrates clear lungs with no interstitial or air space abnormalities.

A CXR 10 days after her initial presentation (Fig. 2A) revealed interval development of bilateral air space disease consistent with mild pulmonary edema or pneumonia. She was started on a 7-day course of levofloxacin for empiric coverage of pneumonia. A chest CT (Fig. 2B) demonstrated interval development of bilateral ground glass opacities and interstitial thickening consistent with acute pulmonary edema. A follow-up CXR 6 days later and 16 days after her initial presentation (Fig. 3) showed increasing prominence of the interstitial thickening consistent with ongoing interstitial pneumonitis. The air space disease had largely resolved. Pulmonary function tests were significant for decreased diffusing capacity of only 25% on diffusing capacity of the lung for carbon monoxide testing and 49% on diffusing capacity to alveolar volume testing, again suggestive of an interstitial lung process.

View larger version (81K): [in this window] [in a new window]   Figure 2. Imaging 10 days after presentation. Posterior–anterior chest radiograph (A) demonstrates bilateral patchy ground glass opacities involving the mid- to lower lungs. The heart size is normal and no pleural effusions are seen. A high-resolution lung window image from a computed tomography scan (B) again demonstrates bilateral patchy ground glass air space opacities and reticular thickening with no zonal predominance.

View larger version (90K): [in this window] [in a new window]   Figure 3. Imaging 16 days after presentation. Posterior–anterior (A) and lateral (B) chest radiographs demonstrate thickened interstitial opacities and an interval decrease in air space disease.

Over the week, the patient was able to wean her oxygen requirement down to 95% on 3 l via nasal cannula (and falling to 82% on room air). She continued her steroid course with a slow taper over 3 weeks. She was discharged home with home oxygen, and instructed to maintain oxygen saturation >90%.

	DISCUSSION

Top Learning Objectives Abstract Introduction Case Report Discussion Author Contributions References

 
Gemcitabine as a single agent or in combination with other chemotherapeutic agents is increasingly used in the treatment of epithelial ovarian cancer, the most common type of ovarian cancer. Several phase I–II trials have reported an overall response rate of 13%–24% with single-agent treatment and remission rates of up to 60% with combination therapy [11]. Several studies are currently evaluating gemcitabine as a second-line agent for platinum-resistant or refractory ovarian cancer.

Gemcitabine may exert some very toxic side effects. Gemcitabine-induced lung toxicity is a diagnosis of exclusion. Alternative conditions must be ruled out, including pneumonia, pulmonary embolus, cardiac-related respiratory distress, malignancy, lymphangitic carcinomatosis, and exacerbation of chronic lung conditions. The diagnosis, nevertheless, must be made promptly, or Gemzar lung may be quickly fatal.

Our patient's respiratory decline appeared to be secondary to gemcitabine. The time course of treatment to toxicity was relatively short, occurring over 2 months. This temporal progression was similar to those previously reported, in the range of 3–12 weeks from treatment initiation [3, 6, 8]. These changes were corroborated by imaging studies, which revealed the development of interstitial pneumonitis over 2–3 weeks. Other causes of noniatrogenic interstitial pneumonitis are unlikely to develop within this short time frame. Furthermore, the patient's elevated alkaline phosphatase levels directly correlated with receiving gemcitabine. Elevated alkaline phosphatase levels occur in approximately 70% of gemcitabine-treated patients [12]. It is unclear whether alkaline phosphatase is related to lung toxicity or is a coincidental effect of gemcitabine, though they seemed to occur simultaneously in this patient. In a recent review, the onset of toxicity occurred at a median of the second cycle, though it also occurred after the first administration or several cycles thereafter [8].

Beyond the timing of these events, in our patient, multiple imaging findings were consistent with gemcitabine pulmonary toxicity. Specifically, diffuse ground glass opacities and septal thickening were present throughout the lungs, which are common in gemcitabine-induced lung toxicity. Additionally, the lack of cardiac enlargement or vascular engorgement minimizes a cardiac etiology [9]. The development of interstitial pneumonitis was confirmed by new findings on CXR.

The mechanism of toxicity in gemcitabine-induced lung toxicity remains unclear. Gemcitabine may cause increased capillary permeability, resulting in pulmonary edema. A cytokine-mediated, inflammatory reaction may lead to acute respiratory distress syndrome (ARDS) [2, 4, 6]. Such damage has been confirmed by postmortem examination as well as bronchial biopsies, showing patchy alveolar hemorrhage and edema with alveolar wall inflammation, edema and focal hyaline membrane formation, and hyperplasia of type II pneumocytes [2, 5, 8]. These findings are similar to those of cytarabine lung toxicity [4]. Possibly, concurrent elevations in liver enzymes reflect a more mild inflammatory process of the liver, causing a less severe but similar reaction to the tissues in the lungs. The interstitial inflammatory process could be associated with cytokines including tumor necrosis factor or various interleukins. There may be a spectrum of disease from interstitial damage to ARDS.

Gemcitabine-induced lung toxicity must be recognized and treated rapidly in order to prevent mortality. Typically, high-dose steroids, including hydrocortisone, methylprednisolone, or dexamethasone are given, and tapered over the course of several weeks [1]. Gemcitabine must be stopped to prevent further injury. If restarted, there is a potential for further lung injury [10]. In other reports, diuretics (furosemide) as well as empiric trials of antibiotics have been administered [3, 4, 6]. As in other published cases, our patient recovered with a short course of steroids, although her cancer continued to progress.

Gemcitabine is becoming an increasingly popular treatment of malignant solid tumors. This case report illustrates a rare, but serious side effect associated with gemcitabine. Clinicians must be cognizant of this condition to prevent further morbidity and mortality in these cancer patients.

	AUTHOR CONTRIBUTIONS

Top Learning Objectives Abstract Introduction Case Report Discussion Author Contributions References

 
Conception/design: Annekathryn Goodman

Financial support: Annekathryn Goodman

Administrative support: Annekathryn Goodman

Provision of study materials or patients: Susanna Lee, Annekathryn Goodman

Collection/assembly of data: Emily Ko, Susanna Lee, Annekathryn Goodman

Data analysis and interpretation: Emily Ko, Susanna Lee, Annekathryn Goodman

Manuscript writing: Emily Ko, Susanna Lee, Annekathryn Goodman

Final approval of manuscript: Emily Ko, Susanna Lee, Annekathryn Goodman

	REFERENCES

Top Learning Objectives Abstract Introduction Case Report Discussion Author Contributions References

 

1. Lorusso D, Ferrandina G, Fruscella E et al. Gemcitabine in epithelial ovarian cancer treatment: Current role and future perspectives. Int J Gynecol Cancer 2005;15:1002–1013.[CrossRef][Medline]
2. Pavlakis N, Bell DR, Millward MJ et al. Fatal pulmonary toxicity resulting from treatment with gemcitabine. Cancer 1997;80:286–291.[CrossRef][Medline]
3. Gupta N, Ahmed I, Steinberg H et al. Gemcitabine-induced pulmonary toxicity: Case report and review of the literature. Am J Clin Oncol 2002;25:96–100.[CrossRef][Medline]
4. Linskens RK, Golding RP, van Groeningen CJ et al. Severe acute lung injury induced by gemcitabine. Neth J Med 2000;56:232–235.[CrossRef][Medline]
5. Marruchella A, Fiorenzano G, Merizzi A et al. Diffuse alveolar damage in a patient treated with gemcitabine. Eur Respir J 1998;11:504–506.[Abstract]
6. Rosado MF, Kett DH, Schein RM et al. Severe pulmonary toxicity in a patient treated with gemcitabine. Am J Clin Oncol 2002;25:31–33.[CrossRef][Medline]
7. Roychowdhury DF, Cassidy CA, Peterson P et al. A report on serious pulmonary toxicity associated with gemcitabine-based therapy. Invest New Drugs 2002;20:311–315.[CrossRef][Medline]
8. Barlesi F, Villani P, Doddoli C et al. Gemcitabine-induced severe pulmonary toxicity. Fundam Clin Pharmacol 2004;18:85–91.[CrossRef][Medline]
9. Boiselle PM, Morrin MM, Huberman MS. Gemcitabine pulmonary toxicity: CT features. J Comput Assist Tomogr 2000;24:977–980.[CrossRef][Medline]
10. Sauer-Heilborn A, Kath R, Schneider CP et al. Severe non-haematological toxicity after treatment with gemcitabine. J Cancer Res Clin Oncol 1999;125:637–640.[CrossRef][Medline]
11. Hansen SW. Gemcitabine in the treatment of ovarian cancer. Int J Gynecol Cancer 2001;11(suppl 1):39–41.[Medline]
12. Gemzar (Gemcitabine HCl) for injectionAccessed June 30, 2008Available at http://www.fda.gov/cder/foi/020509s039lbl.pdf.

This Article Abstract Full Text (PDF) All Versions of this Article: theoncologist.2008-0049v1 13/7/807    most recent eLetters: Submit a response to this article Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Ko, E. Articles by Goodman, A. Search for Related Content PubMed PubMed Citation Articles by Ko, E. Articles by Goodman, A.